S0355 Ixabepilone in Treating Patients With Advanced Solid Tumors or Lymphomas and Liver Dysfunction

A Phase I Pharmacokinetic Study Of Epothilone B Analogue BMS-247550 (NSC 710428D) In Patients With Advanced Malignancies And Varying Levels Of Liver Dysfunction

RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die.

PURPOSE: This phase I trial is studying the side effects and best dose of ixabepilone in treating patients with advanced solid tumors or lymphomas and liver dysfunction.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Small Intestine Cancer; Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Drug: BMS-247550

Detailed Description

OBJECTIVES:

• Determine the levels of hepatic impairment at which dose modifications of ixabepilone are required in patients with advanced solid tumors or lymphomas and varying levels of liver dysfunction.
• Determine the effect of hepatic dysfunction on the plasma pharmacokinetics of this drug in these patients.
• Determine the toxic effects of this drug at varying levels of hepatic dysfunction in these patients.

OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to liver function (normal vs mild dysfunction vs moderate dysfunction vs severe dysfunction).

Patients receive ixabepilone IV over 3 hours on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of ixabepilone until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, at least 6 but no more than 12 patients are treated at the recommended phase II dose.

Patients are followed for 30 days.

PROJECTED ACCRUAL: A total of 12-84 patients (6-12 for stratum 1; 2-18 for stratum 2; 2-24 for stratum 3; and 2-30 for stratum 4) will be accrued for this study within 12 months.

• Study Type: Interventional
• Enrollment (Actual): 78
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010-3000
      • City of Hope Comprehensive Cancer Center
    • Los Angeles, California, United States, 90089-9181
      • USC/Norris Comprehensive Cancer Center and Hospital
    • Sacramento, California, United States, 95817
      • University of California Davis Cancer Center
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Cardinal Bernardin Cancer Center at Loyola University Medical Center
  • Kansas
    • Kansas City, Kansas, United States, 66160-7357
      • Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
    • Cleveland, Ohio, United States, 44106
      • Case Comprehensive Cancer Center
    • Independence, Ohio, United States, 44131
      • Community Oncology Group at Cleveland Clinic Cancer Center
    • Wooster, Ohio, United States, 44691
      • Cleveland Clinic - Wooster
  • Texas
    • Fort Sam Houston, Texas, United States, 78234
      • Brooke Army Medical Center
    • Lackland AFB, Texas, United States, 78236
      • Wilford Hall Medical Center
    • San Antonio, Texas, United States, 78229-3900
      • University of Texas Health Science Center at San Antonio
  • Washington
    • Bellingham, Washington, United States, 98225
      • St. Joseph Hospital Community Cancer Center
    • Bremerton, Washington, United States, 98310
      • Olympic Hematology and Oncology
    • Mt. Vernon, Washington, United States, 98273
      • Skagit Valley Hospital Cancer Care Center
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
    • Seattle, Washington, United States, 98104
      • Fred Hutchinson Cancer Research Center
    • Seattle, Washington, United States, 98122-4307
      • Swedish Cancer Institute at Swedish Medical Center - First Hill Campus
    • Seattle, Washington, United States, 98195-6043
      • University Cancer Center at University of Washington Medical Center
    • Seattle, Washington, United States, 98104-1387
      • Group Health Central Hospital
    • Sedro-Wooley, Washington, United States, 98284
      • North Puget Oncology at United General Hospital
    • Spokane, Washington, United States, 99202
      • Cancer Care Northwest - Spokane South
    • Wenatchee, Washington, United States, 98801-2028
      • Wenatchee Valley Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed solid tumor or lymphoma for which standard curative or palliative measures do not exist or are no longer effective

  • Pathological confirmation of diagnosis not required in patients with liver mass, raised alpha-fetoprotein levels (at least 500 ng/mL), and positive serology for hepatitis consistent with a diagnosis of hepatocellular carcinoma
  • Any solid tumor or lymphoma tumor type eligible
  • Must have had thoracic and upper abdominal CT scan, including entire liver and adrenals, within 28 days before study entry

• Patients with glioma or brain metastases must be on a stable dose of corticosteroids and be seizure-free for the past month

  • Prior whole brain or gamma knife radiotherapy required for known brain metastases
  • No unstable or untreated (non-irradiated) brain metastases

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Zubrod 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• No active hemolysis

Hepatic

• See Disease Characteristics
• Patients with biliary obstruction for which a shunt has been placed are allowed if shunt is in place for at least 10 days and liver function is stable
• Abnormal liver function (bilirubin and SGOT) allowed regardless of cause (metastases or other causes)
• No evidence of biliary sepsis

Renal

• Creatinine no greater than 1.5 mg/dL

Cardiovascular

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Other

• No concurrent uncontrolled illness
• No ongoing or active infection
• No uncontrolled diarrhea
• No peripheral neuropathy grade II or greater
• No psychiatric illness or social situation that would preclude study compliance
• HIV negative
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent immunotherapy for malignancy

Chemotherapy

• More than 2 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• No other concurrent chemotherapy for malignancy

Endocrine therapy

• See Disease Characteristics
• No concurrent oral contraceptives

• No concurrent hormone therapy for malignancy

  • Concurrent luteinizing hormone-releasing hormone agonists allowed

Radiotherapy

• See Disease Characteristics
• More than 4 weeks since prior radiotherapy and recovered
• No concurrent radiotherapy for malignancy

Surgery

• More than 2 weeks since prior major surgery

Other

• Recovered from prior therapy
• No concurrent medications that are known to be inhibitors of CYP3A4

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: treatment; Single-arm, dose-escalation of BMS-247550	Drug: BMS-247550; BMS-247550 as a 3-hour infusion on Day 1 of a three-week cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
dose defining	Treatment delays >2 weeks constitute a DLT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression	20% increase in the sum of longest diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline.	30 days after going off study
Symptomatic deterioration	Global deterioration of health status requiring discontinuation of treatment without objective evidence of progression.	30 days after going off study

Collaborators and Investigators

• Sponsor: Southwest Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Chris H. Takimoto, MD, PhD, Institute for Drug Development

Publications and helpful links

General Publications

• Takimoto CH, Liu PY, Lenz H, et al.: A phase I pharmacokinetic (PK) study of the epothilone B analogue, ixabepilone (BMS-247550) in patients (pts) with advanced malignancies and varying degrees of hepatic impairment. A SWOG Early Therapeutics Committee and NCI Organ Dysfunction Working Group Trial. [Abstract] J Clin Oncol 24 (Suppl 18): A-2004, 2006.

Study record dates

Study Major Dates

• Study Start: October 1, 2003
• Primary Completion (Actual): September 1, 2006
• Study Completion (Actual): December 1, 2007

Study Registration Dates

• First Submitted: November 12, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): April 3, 2015
• Last Update Submitted That Met QC Criteria: April 1, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: unspecified adult solid tumor, protocol specific; stage IV adult immunoblastic large cell lymphoma; recurrent adult diffuse large cell lymphoma; recurrent adult immunoblastic large cell lymphoma; recurrent adult Burkitt lymphoma; recurrent adult Hodgkin lymphoma; recurrent adult diffuse small cleaved cell lymphoma; recurrent adult diffuse mixed cell lymphoma; stage IV adult diffuse small cleaved cell lymphoma; stage IV mantle cell lymphoma; recurrent marginal zone lymphoma; recurrent small lymphocytic lymphoma; stage IV small lymphocytic lymphoma; stage IV marginal zone lymphoma; nodal marginal zone B-cell lymphoma; splenic marginal zone lymphoma; recurrent adult lymphoblastic lymphoma; recurrent mantle cell lymphoma; stage IV cutaneous T-cell non-Hodgkin lymphoma; recurrent cutaneous T-cell non-Hodgkin lymphoma; small intestine lymphoma; stage IV adult lymphoblastic lymphoma; stage IV adult T-cell leukemia/lymphoma; recurrent adult T-cell leukemia/lymphoma; intraocular lymphoma; angioimmunoblastic T-cell lymphoma; anaplastic large cell lymphoma; primary central nervous system lymphoma; recurrent grade 1, 2, or 3 follicular lymphoma; stage IV adult diffuse large cell or mixed cell lymphoma; stage IV adult Burkitt lymphoma or Hodgkin lymphoma; stage IV grade 1, 2, or 3 follicular lymphoma; extranodal marginal zone B-cell lymphoma of MALT
• Additional Relevant MeSH Terms: Digestive System Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Liver Diseases; Lymphoma; Intestinal Neoplasms
• Other Study ID Numbers: S0355 (Other Identifier: SWOG); U10CA032102 (U.S. NIH Grant/Contract); P30CA016087 (U.S. NIH Grant/Contract); U01CA076642 (U.S. NIH Grant/Contract)